In the field of vaccines, it is well known that the efficacy of the vaccine composition is essentially due to the mixture of the antigen used with an adjuvant. Adjuvants for vaccines have been used for many years and are defined as compositions which, when combined with an antigen, produce an immune response greater than that of the antigen alone.
The immunogenic power of a vaccine without an adjuvant is weak as a rule, particularly when an inactivated virus is involved or when the antigen is simply a peptide or a protein and does not in itself make it possible to induce a protective response.
Extensive research has been performed to obtain satisfactory adjuvants which, ideally, ought to have the following properties:                they induce a major immune response, particularly with a minimal antigen dose;        they induce a mixed immune response (humoural and cellular) to promote and establish a memory response;        they are perfectly tolerated and devoid of toxicity;        they are, if possible, constituted of excipients commonly used in the pharmaceutical field, more specifically that of injectable drugs;        they are easy to administer, with the aid of a syringe for example and if possible, to directly fill into ready-to-use syringes;        they are easy to combine with various different antigens to allow standardization of production of different vaccines;        they are easy to produce on an industrial scale using a manufacturing process which is easy to master;        
A multitude of adjuvants of various different types and origins is known.
Alum (aluminium phosphate and hydroxide) is an adjuvant the use of which is widespread in human and veterinary vaccines.
Other adjuvants are known and used for research such as Freund's adjuvant constituted of a mixture of mineral oil and killed mycobacterium. This adjuvant is extremely effective and products pronounced immune responses. Its poor tolerance, however, limits its use to research in laboratory animals.
Various patents describe adjuvant compositions for vaccines.
U.S. Pat. No. 4,788,056 describes a combined vaccine against herpes and E. coli intended for vaccination of livestock. It mentions various different possible adjuvants, including oil/water emulsions or water/oil emulsions based on certain oils such as MIGLYOL® (medium-chain triglycerides) or surfactants such as polysorbate without, however, indicating any precise formulation of the adjuvant. Conventional emulsions are, however, involved in which the dispersed phase exists in the form of droplets. Furthermore, no indication is given with regard to the effect of the adjuvant on the immunogenic power of the vaccine.
U.S. Pat. No. 5,688,761 describes a water in oil microemulsion formulation which converts into an oil in water system by addition of an aqueous fluid, which results in release of the protein contained in the aqueous phase. The advantage of microemulsions is their spontaneous formation and their physical stability. The oils are well tolerated via the injectable route such as medium-chain mono and triglycerides. They are emulsified with the aqueous phase by means of the use of conventional surfactants known by one skilled in the art such as sorbitan esters or polysorbates. Their dilution by biological fluids during their injection results in inversion of the phases and, therefore, release of the biological agent incorporated in the aqueous phase. Certain examples of formulation show an increase in the activity of biological agents incorporated into the described formulation. However, the examples provided do not concern the field of vaccines.
U.S. Pat. No. 5,744,137 describes use of non-mineral oils in vaccines, in addition to vaccines in the form of water in oil emulsions containing a mixture of at least two surfactants chosen from among ethoxylated castor oil, propylene glycol laurate, propylene glycol caprylate and isosteryl diglyceryl succinate. The chosen oils are of animal or plant origin to limit in as far as possible the tissue reaction related to administration of poorly tolerated mineral oils.
U.S. Pat. No. 5,961,960 describes a vaccine adjuvant presented in the form of an oil in water submicroemulsion comprising an emulsifier (a phospholipid is involved), a non-ionic surfactant and an oil. The high cost of phospholipids restricts the applications of this invention however.
US 2003/0119774 describes a composition consisting of biphasic lipid vesicles allowing improvement of the immune response induced by an antigen.
US 2003/0175309 describes and adjuvant containing lecithin, an oil and an amphiphilic surfactant capable of forming a vaccine in the form of a stable oil in water emulsion which makes it possible to minimize local reactions in the infected animal.
WO 99/61003 describes a system for delivering active substances comprising a drug reserve in closely compacted solid form with an isotropic structure in the solid state. This system is adequate for delivering active substances by inhalation. The active substance comes in the form of liposomes, the liposomes being subsequently compacted to form the solid delivery system described.
EP 0 398 287 describes a pharmaceutical composition in the form of an isotropic solution consisting of one or several active substances and a medium which solidifies between 20° C. and 80° C. (particularly at ambient temperature) and is soluble in water.
The fact remains that there is a constantly recurrent need in the vaccine industry for new adjuvants presenting the properties listed above. In particular, the need remains to provide adjuvants allowing a major increase in the immunogenic power of the antigen. An advantage of such adjuncts adjuvants lies in the fact that they allow administration of low doses of antigen while retaining a satisfactory immune response.
It is particularly desirable to have such compositions available when the antigen is costly or difficult to produce in sufficient quantities or when a simple peptide or antigens obtained by synthesis or recombination is involved.